1. Technical Field of the Invention
The present invention relates to dermatological compositions comprising, formulated into a physiologically acceptable medium, at least one retinoid, dispersed benzoyl peroxide and at least one carrageenan.
2. Description of Background and/or Related and/or Prior Art
The administration of several categories of active principles is a therapeutic tool to which recourse is frequently had, in particular in the treatment of dermatological disorders.
Specifically, it is known to administer peroxides, vitamins D and retinoids in the topical treatment of various pathologies related to the skin or mucous membranes, in particular acne.
The combination of several local treatments (antibiotics, retinoids, peroxides, zinc) is also employed in dermatology to make it possible to enhance the effectiveness of the active principles and to reduce their toxicity (Cunliffe W. J., J. Dermatol. Treat., 2000, 11 (Suppl. 2), S13-S14).
The multiple application of different dermatological products may be rather burdensome and demanding for the patient.
The interest in attempting to obtain a novel treatment which is effective with regard to dermatological conditions in a stable composition which offers a good cosmetic quality, which makes possible a single application and which makes possible administration which is agreeable to the patient is thus understood.
There is nothing among this range of therapies provided to one skilled in the art which would encourage him to combine, in the same composition, benzoyl peroxide, a retinoid and several gelling agents.
This is because the formulation of such a composition presents several problems.
First of all, the effectiveness of the benzoyl peroxide is related to its decomposition when it is brought into contact with the skin. This is because it is the oxidizing properties of the free radicals produced during this decomposition which result in the desired effect. Consequently, to maintain the optimum effectiveness of the benzoyl peroxide, it is important to prevent it from decomposing before use, that is to say during storage. In point of fact, benzoyl peroxide is an unstable chemical compound, which makes it difficult to formulate it into finished products.
The solubility and the stability of benzoyl peroxide have been studied by Chellquist et al. in ethanol, propylene glycol and various mixtures of polyethylene glycol 400 (PEG 400) and water (Chellquist E. M. and Gorman W. G., Pharm. Res., 1992, Vol. 9, 1341-1346). It turns out that benzoyl peroxide is particularly soluble in PEG 400 and ethanol.
This document furthermore specifies that the stability of benzoyl peroxide is strongly influenced by the chemical composition of the formulation and by the storage temperature. Benzoyl peroxide is highly reactive and decomposes in solution at low temperature due to the instability of its peroxide bond.
The authors thus determine that benzoyl peroxide in solution decomposes more or less rapidly in all the solvents studied according to the type of solvent and its concentration.
The decomposition times of benzoyl peroxide in PEG 400 (0.5 mg/g), in ethanol and in propylene glycol are 1.4, 29 and 53 days respectively at 40° C. Such a decomposition does not make possible the formulation of a product intended for sale.
Furthermore, it is known that benzoyl peroxide is more stable in water and propylene glycol when it is in suspension (i.e., in the dispersed form), since it is not decomposed after storing for 90 days in these solvents.
Thus, to limit the problem of rapid instability of benzoyl peroxide in solution, it has proven to be advantageous to formulate benzoyl peroxide in the dispersed form.
However, this type of formulation is not completely satisfactory insofar as the benzoyl peroxide is still found to be decomposed in the finished product.
Another difficulty to be overcome in the formulation of a composition comprising both benzoyl peroxide and a retinoid is that the majority of retinoids are particularly sensitive to natural oxidation, to visible light and ultraviolet radiation. As benzoyl peroxide is a strong oxidizing agent, the chemical compatibility of these two compounds in one and the same formulation presents numerous problems of stability from the physical and chemical viewpoint.
A stability study was carried out on two retinoids by combining two commercial products, one comprising a retinoid (tretinoin or adapalene) and the second based on benzoyl peroxide (B. Martin et al., Br. J. Dermatol., (1998) 139, (suppl. 52), 8-11).
The presence of benzoyl peroxide in the formulation causes very rapid decomposition of the oxidation-sensitive retinoids: 50% of the tretinoin is measured as decomposing in 2 hours and 95% in 24 hours. In the composition comprising adapalene as retinoid, no decomposition of the adapalene was measured during 24 hours.
This study confirms that benzoyl peroxide is decomposed and decomposes oxidation-sensitive retinoids over time by gradually releasing benzoic acid in finished products.
In point of fact, it is clear that the decomposition of benzoyl peroxide and retinoids is not desirable insofar as it is harmful to the effectiveness of the composition in which they are present.
Nothing thus prompted the combining of these two active agents to obtain a stable composition of gel or emulsion type, it being known that it was conventionally recognized that the presence of benzoyl peroxide chemically and physically destabilized compositions of these types.
In particular, the formulation as a gel of benzoyl peroxide and a retinoid is advantageous for topical treatments, such as that of acne, as it avoids in particular leaving a greasy feel remaining on the skin.
More specifically, the term “gel” means a system comprising at least one thermodynamically stable phase (in general one or two phases) resulting from the coagulation as a three-dimensional network of a colloidal solution. More precisely, an aqueous gel corresponds to a composition comprising, in an aqueous phase, a viscoelastic mass formed from colloidal suspensions (carrageenan or combination of a carrageenan with another gelling agent).
In particular, the formulation as a “light” emulsion of benzoyl peroxide and a retinoid is advantageous for topical treatments, such as that of acne, as, in the case of a “light” emulsion, it contributes emollience while avoiding leaving an excessively greasy feel remaining on the skin.
“Light” emulsion means an emulsion comprising a low proportion of fatty phase, the aqueous phase remaining predominant. An emulsion is a system comprising two fluids which are insoluble or only slightly soluble in one another, and in which one of the fluids is dispersed in the other as microscopic particles. Preferably, the emulsions used comprise or do not comprise at least one emulsifier, a polar hydrophilic phase, preferably aqueous phase, and a nonpolar fatty phase. Preferably, they are provided in the form of “oil-in-water” (O/W) or “water-in-oil” (W/O) emulsions.
In point of fact, another difficulty to be overcome in the formulation of a composition comprising in particular benzoyl peroxide, when it occurs in the gel or emulsion form, is that the gelling agents of the aqueous phase are destabilized by the benzoic acid released during the decomposition of the benzoyl peroxide.
Specifically, the gelling agents of the aqueous phase most commonly used with benzoyl peroxide are acrylic acid polymers (carbomer).
In point of fact, the use of carbomers in compositions of aqueous gel type does not provide good results in terms of chemical stability of the benzoyl peroxide and in terms of rheological stability. As described by Bollinger (Bollinger, Journal of Pharmaceutical Science, 1977, Vol. 5), a loss of 5 to 20% of benzoyl peroxide after 2 months at 40° C., depending on the neutralizing agent of the carbomer used, was observed. Furthermore, the release of benzoic acid brings about depolymerization of the carbomers, giving a fall in viscosity which may bring about phase separation.
This instability of benzoyl peroxide gels (as such or as gelled aqueous phase of an emulsion) is thus harmful to their effectiveness and to their cosmetic quality.
Furthermore, a finished product, in particular when it concerns pharmaceutical or cosmetic compositions, must maintain, throughout its lifetime, precise physicochemical criteria which make it possible to guarantee its pharmaceutical and cosmetic quality. Among these criteria, it is necessary for the rheological properties to be retained. They define the behavior and the texture of the composition during application but also the properties of release of the active principle [SFSTP Commission report 1998] and the homogeneity of the product when the active principles are present therein in the dispersed state.
Need thus exists for a physically and chemically stable composition of gel or emulsion type comprising benzoyl peroxide and a retinoid.